Amyotrophic lateral sclerosis (ALS) is considered the most devastating neurodegenerative disease. Patients suffer progressive functional loss, including loss of speech, swallowing, mobility, and respiration that leads to death on average 2 to 4 years after diagnosis. Except for aggressive symptomatic care, there are no effective treatments. More than 50 clinical trials based on plausible hypotheses of disease mechanisms have failed except for riluzole. Identified inherited pathogenic mutations account for ~10% of all ALS cases; the cause of most sporadic cases is unknown. ALS is now considered to be potentially caused by a combination of both genetic and environmental risk factors. Our overall hypothesis is that individual environmental risk factors reported to be associated with ALS act via a common mechanism, specifically oxidative stress (OS). Our NIEHS-funded prospective multicenter cohort study of ALS (ALS COSMOS), which investigates the extent to which multiple risk factors associated with OS are also associated with ALS progression, is in its final stages. Our current ARREST ALS project expands ALS COSMOS at a national level through the National ALS Registry, using structured telephone interviews and one-time urine and saliva collection. Now, we propose a set of well-designed, high-quality, case-control studies nested within ARREST ALS. We specifically aim: 1. To evaluate environmental and other risk factors in a population-based case-control study nested within the ARREST ALS study of the National ALS Registry. The cases (150 patients) will be identified in the on- going ARREST ALS project. We will match 2 controls to each case based on sex, age ( 5 years), race/ethnicity, and geographic area of residence. We will administer our well-validated, structured interview to determine cognitive function and obtain data on early life events and environmental, residential, occupational, dietary, lifestyle, and psychological factors. Dietary questionnaire data, first-void urine samples to measure OS markers, and saliva DNA will be collected; 2. To evaluate early life and late life environmental and other risk factors in a sibling-based, case-control study. We will identify a same-sex sibling who agrees to participate and is closest in age to the case. We estimate that 80% of cases will have a sibling who meets these criteria. They will receive the same risk factor assessment and provide saliva and urine samples as the population controls. 3. To evaluate individual or aggregate environmental risk factors between cases and controls at different stages of life and to investigate the significance of the urinary OS biomarker in relation to ALS and environmental risk factors. We will analyze risk factors at different stages of life in the two control groups combined in comparison to the cases and further analyze OS biomarkers in relation to risk factors. In summary, carefully designed population-based and sibling-based case-control studies nested within ARREST ALS will reveal entirely new and unique data concerning environmental risk factors, disease progression, and the potential cause(s) of ALS.